Epigenetic silencing of genes involved in hematopoietic differentiation and mutations in genes encoding tyrosine kinase receptors (TKRs) involved in hematopoietic cell proliferation are critical players in myeloid leukemogenesis. Although novel compounds targeting the aberrant features of kinome (TKR inhibitors) and epigenome (DNMT inhibitors) in AML have been tested in clinical trials, the response to them as single agents has been short-lived, suggesting that a single mechanism may not be sufficient to overcome AML. We reasoned that concurrent molecular targeting may result in better antileukemic activity compared with single target approaches. In order to develop such approach, the mechanism of leukemogenesis needs to be understood. Recently, we have shown that miR-29b is central to regulation of both epigenome (DNA methylation) and kinome in AML by targeting and repressing the expression of TKRs (KIT and FLT3) and DNMTs. Furthermore, we showed that high levels of miR-29b are predictive of sensitivity to the hypomethylating agent decitabine in older AML patients. In preclinical studies, we showed that endogenous miR-29b can be pharmacologically increased with TKI (sorafenib), Sp1/NFkB interfering compounds (bortezomib) and histone deacetylase inhibitors. Therefore, we hypothesize here that a pre-emptive pharmacologic increase of otherwise low endogenous levels of miR-29b cells will enhance the antileukemia activity of decitabine and lead to a more durable clinical response in older AML patients. We propose to pursue this strategy through the following specific aims: Specific Aim #1: To conduct a Phase 1 clinical trial with bortezomib and sorafenib in combination followed by decitabine in elderly (>60) AML patients in order to determine: (a) the biologically effective and tolerable dose (BETD) of bortezomib/sorafenib combination; (b) a phase II recommended dose and (c) pharmacodynamic (PD) endpoints related to the targeting activity of miR-29b. Specific Aim #2: To conduct a Phase 2 clinical trial with bortezomib and sorafenib followed by decitabine in newly diagnosed elderly (>60) AML patients in order to: (a) assess clinical efficacy of the combination;(b) to validate the biologic mechanisms of activity of the combination by correlating biologic endpoints (e.g,miR-29b,) with clinical response. Specific Aim #3: To investigate whether HDAC inhibitors (i.e., AR42), which also disrupts the HDAC/Sp1-NF:B complex, enhance miR-29b expression when combined with bortezomib and sorafenib in the preclinical setting and in turn improve even further the response rate to decitabine. We will conduct preclinical in vivo studies in order to: (a) determine the optimal dose of AR42 that leads to the highest expression of miR-29b by performing PK/PD modeling; (b) asses survival of the combination AR42/bortezomib/sorafenib followed by decitabine as compared with bortezomib/sorafenib or AR42 alone followed by decitabine; (c) recommendation of an optimal dose/schedule of the AR42/bortezomib/sorafenib followed by decitabine for testing in the phase I setting in humans.